During his lifetime, Sobukwe was considered to be so dangerous by the National Party government that its parliament enacted the "Sobukwe clause", a statute which on its face seemed to grant broadly applicable powers, but was specifically intended to authorise the arbitrary extension of Sobukwe's imprisonment.

He was a strong believer in an Africanist future for South Africa and rejected any model suggesting working with anyone other than Africans, defining African as anyone who lives in and pays his allegiance to Africa and who is prepared to subject himself to African majority rule. He later left the ANC to form the Pan Africanist Congress (PAC), and was elected its first President in 1959.[3]:421

Sobukwe became known as the Professor or simply "Prof" to his close comrades and followers, a testament to his educational achievements and powers of speech and persuasion. He spoke of the need for black South Africans to "liberate themselves" without the help of non-Africans. He defined non-Africans as anyone who lives in Africa or abroad Africa and who does not pay his allegiance to Africa and who is not prepared to subject himself to African majority rule. His strong convictions and active resistance inspired many other individuals and organisations involved in the anti-apartheid movement, notably the Black Consciousness Movement.

At Fort Hare, where generations of young Black South Africans were exposed to politics, he joined the African National Congress Youth League (ANCYL) in 1948. The organisation had been established on the university campus by Godfrey Pitje, who later became its president. In 1949 Sobukwe was elected as the first president of the Fort Hare Students' Representative Council, where he proved himself to be a good orator.

In 1950 Sobukwe was appointed as a teacher at a high school in Standerton, a position he lost when he spoke out in favour of the Defiance Campaign in 1952. He was, however, reinstated. During this period he was not directly involved with mainstream ANC activities, but still held the position of secretary of the organisation’s branch in Standerton.

In 1954 after moving to Johannesburg Sobukwe became a lecturer of African Studies at the University of the Witwatersrand.[2] During his time in Johannesburg he edited The Africanist newspaper and soon began to criticise the ANC for allowing itself to be dominated by what he termed "liberal-left-multi-racialists". He strongly believed in non-racialism. He was an ardent supporter of Africanist views about liberation in South Africa and rejected the idea of working with Whites.

Robert Mangaliso Sobukwe, in the 1950s, has the same effect that Malcolm X’s movement had. He argued that whites should be excluded from the ANC as it was impossible for the relationship between whites and blacks until further progress had been made. He argued that a reliance on whites would disempower the realization that many of these Africans had, that they had the power to overtake a society that had been taken from them. The fight in the ANC was brutal, causing a fair amount of violence which lead to the creation of the Pan-Africanist Congress. PAC excluded white men. A goal of PAC was to get rid of the servant mentality through the identification of other African Nationalist movements and through, what they called it, "self-identification". To know that there were others out, trying to achieve the same things, gave the Africanists a real sense of power and unification. This sense of unification and power would end in 1960 in the town of Sharpville. A protest by PAC would become a police massacre. In the massacre sixty-nine people were killed and Sobukwe was taken without a fair trial in addition to both the ANC and PAC being banned. Other organizations were inspired by the actions of Sobukwe.<Nation. 4/1/1978, Vol. 226 Issue 12, p368-370. 3p.>

On 21 March 1960, the PAC led a nationwide protest against the hated Pass Law which required black people to carry a pass book at all times. Sobukwe led a march to the local police station at Orlando, Soweto, in order to openly defy the laws.[2] He was joined en route by a few followers and, after presenting his pass to a police officer, he purposely made himself guilty under the terms of the Pass Law of being present in a region/area other than that allowed as per his papers. In a similar protest on the same day in Sharpeville, police opened fire on a crowd of PAC supporters, killing 69 in the Sharpeville Massacre.

Following his arrest, Sobukwe was charged with and convicted of incitement, and sentenced to three years in prison. After serving his sentence, he was interned on Robben Island. The new General Law Amendment Act was passed, allowing his imprisonment to be renewed annually at the discretion of the Minister of Justice. This procedure became known as the "Sobukwe clause" and went on for a further three years. Sobukwe was the only person imprisoned under this clause.

Sobukwe was kept in solitary confinement but permitted certain privileges including books, newspapers, civilian clothes, bread, etc. He lived in a separate area on the island where he was strictly prohibited from contact with other prisoners. His only contacts with them were through his secret hand signals while outside for exercise. Despite this, he succeeded in giving his approval to the external PAC to adopt a Maoist political program. He studied during this time and received (among others) a degree in economics from the University of London.

It is speculated that Sobukwe was subjected to this special treatment because the South African government had profiled him as a more radical and difficult opponent than the regular ANC prisoners.

Throughout his imprisonment, Sobukwe maintained communication with his friend Benjamin Pogrund who later became his biographer (Sobukwe and Apartheid, Johannesburg: J. Ball, 1990).

Sobukwe was released in 1969. He was allowed to live in Kimberley with his family, but remained under house arrest. Kimberley was suggested as an area where he could not easily foster subversive activities and also a place where he could live and work, while being easily monitored by the state. He was also restricted through a banning order, which disallowed political activities.

Various restrictions barred Sobukwe from travelling overseas, thus curtailing his attempts to further his education. For this same reason, he had to turn down several positions as a teacher at various locations in the United States.

Sobukwe completed his law degree with the help of a local lawyer, in Galeshewe, and he then started his own practice in 1975 in Kimberley.

Due to lung cancer, Sobukwe was hospitalised in 1977. His doctors requested that the authorities allow him freedom of movement on humanitarian grounds. This request was refused indefinitely. He died on 27 February 1978, and was buried in Graaf-Reinet on 11 March 1978.